“The preclinical data did not necessarily support the requirement of these biomarkers, but they were included as a hypothesis-generating component,” said lead investigator Richard S. Finn, MD, Assistant Professor in the Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine, University of California, Los Angeles.

The study was conducted at 50 centers in 12 countries. As reported previously, median progression-free survival (PFS), the primary end point of the study, was doubled in patients receiving palbociclib plus letrozole compared with letrozole alone (20.2 vs 10.2 months; hazard ratio [HR], 0.488; P = .0004), with an acceptable safety profile.2 These results led to accelerated US Food and Drug Administration approval of palbociclib. At the time of the primary PFS analysis, OS data were immature but trended toward improved median OS in the palbociclib plus letrozole arm compared with the letrozole alone arm (37.5 vs 33.3 months; HR, 0.813; P = .42).

Patients in PALOMA-1 were randomized in an open-label fashion to first-line treatment with palbociclib 125 mg daily, plus letrozole 2.5 mg daily, given 3 weeks on followed by 1 week off, or letrozole alone. Baseline characteristics were well-balanced between the 2 arms. Approximately half of the patients in each arm had visceral disease. Approximately half of the study participants had de novo metastatic disease and half had prior systemic treatment, including aromatase inhibitors.

At the December 30, 2016, data cutoff, the median duration of follow-up was 64.7 months, at which time the median OS was 37.5 months in the palbociclib plus letrozole arm versus 34.5 months in the letrozole monotherapy arm (HR, 0.897; P = .281) in an intent-to-treat analysis.

A nonsignificant 4-month improvement in OS was observed in the recipients of palbociclib plus letrozole compared with letrozole alone in women enrolled in part 1 (37.5 vs 33.3 months; HR, 0.837; P = .280). There was no difference in OS between the 2 treatment arms in women enrolled in part 2 of the trial.

Post-study systemic therapy was received by 83% of patients randomized to palbociclib plus letrozole and by 89% of patients randomized to letrozole only.

Dr Finn said most guidelines recommend endocrine therapy as the first-line choice for women with advanced ER-positive breast cancer, thereby delaying the time to chemotherapy and the additional toxicity observed with chemotherapy. There was a 9-month delay in the median time to chemotherapy in patients started on palbociclib in addition to letrozole versus letrozole alone (26.7 vs 17.7 months, respectively). More patients remained on palbociclib and letrozole throughout the duration of the study.

No new toxicities were observed at the latest data cutoff, with the most common adverse events being neutropenia, leukopenia, and fatigue in the combination arm.

“There is no appearance of cumulative toxicity even out over 5 years,” Dr Finn said.

The duration of survival and safety follow-up data in PALOMA-1 are the longest for any cyclin-dependent kinase 4/6 inhibitor in breast cancer. Based on previous analyses and given the longer median postprogression survival, Dr Finn concluded that a larger sample size would be needed to detect a significant difference in OS in the frontline setting in ER-positive breast cancer.

“With that, survival data from the pivotal PALOMA-2 trial are still awaited,” he said.